1. Field of the Invention
The present invention relates generally to the fields of molecular pharmacology and the biochemistry of inflammation. More specifically, the present invention relates to a selective 2-acyloxyphenylalkyl, -alkenyl, -alkynyl, and 2-acyloxyphenylaryl sulfide inhibitors of prostaglandin endoperoxide synthase-2.
2. Description of the Related Art
Prostaglandins, particularly prostaglandin E.sub.2 (PGE.sub.2), are involved in many diverse physiological and pathophysiological functions. These eicosanoids are produced by the action of prostaglandin endoperoxide synthase (PGHS, EC 1.14.99.1) on arachidonic acid. Prostaglandin endoperoxide synthase activity originates from two distinct and independently regulated isozymes, termed as prostaglandin endoperoxide synthase-1 and prostaglandin endoperoxide synthase-2 and are encoded by two different genes (1,2).
Prostaglandin endoperoxide synthase-1 is expressed constitutively and is thought to play a physiological role, particularly in platelet aggregation, cytoprotection in the stomach, and regulation of normal kidney function (FIG. 1). Prostaglandin endoperoxide synthase-2 is the inducible isozyme and expression of prostaglandin endoperoxide synthase-2 is induced by a variety of agents which include endotoxin, cytokines, and mitogens (2,3). Importantly, prostaglandin endoperoxide synthase-2 is induced in vivo to significant levels upon pro-inflammatory stimuli (4).
These discoveries led to the proposal that prostaglandin endoperoxide synthase-1 and prostaglandin endoperoxide synthase-2 serve different physiological and pathophysiological functions. For example, the disruption of beneficial prostaglandin production by all of the currently used non-steroidal antiinflammatory drugs (NSAIDs) results in a mechanism-based toxicity mainly in the gastrointestinal tract and kidney and thus limits their therapeutic usefulness especially when long-term treatment is involved (5-7). As a result of this critical finding, a major discovery effort has been excecuted in the pharmaceutical industry to identify selective and orally active prostaglandin endoperoxide synthase-2 inhibitors because they may provide the desired anti-inflammatory and analgesic properties without the deleterious and sometimes life threatening side effects commonly associated with the existing non-steroidal antiinflammatory drugs.
The prior art is deficient in the lack of selective and orally active prostaglandin endoperoxide synthase-2 inhibitors. The present invention fulfills this longstanding need and desire in the art.